| 1. |
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| 2. |
- Linder, Jan, 1957-, et al.
(author)
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Degenerative changes were common in brain magnetic resonance imaging in patients with newly diagnosed Parkinson's disease in a population-based cohort
- 2009
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In: Journal of Neurology. - Berlin : Springer. - 0340-5354 .- 1432-1459. ; 256:10, s. 1671-1680
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Journal article (peer-reviewed)abstract
- The aim of this study was to investigate newly diagnosed patients with Parkinson's disease (PD) with structural magnetic resonance imaging (MRI), to compare them with healthy controls, to relate the findings to clinical subtypes - tremor dominant (TD) or postural instability and gait difficulty (PIGD) - and to investigate the relationship between both the duration from onset of symptoms to diagnosis and the severity of symptoms and the MRI findings. Patients with a definite PD diagnosis were compared to patients with a probable PD diagnosis. We hypothesized that the PIGD subtype, the probable PD group, a greater symptom severity and a longer symptom duration would all be associated with more frequent pathological findings. Sixty-six PD patients were included and examined with MRI, 35 with the PIGD subtype and 23 with the TD subtype. Fifty-three had definite PD and 13 probable PD. Thirty healthy individuals, matched for age and sex, served as controls. Degenerative changes in the cerebellar cortex and the superior cerebellar peduncle were significantly more common in the probable PD group than in the controls, suggesting the possibility of an emerging atypical parkinsonian disorder. No significant MRI differences were found between definite PD and controls, between definite PD and probable PD, nor between PIGD and TD. No significant associations were found between duration to diagnosis and MRI results, nor between severity of symptoms and MRI results. Thus, although pathological MRI findings were common they can not be used to separate subgroups of PD in newly diagnosed patients.
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| 3. |
- Salami, Alireza, et al.
(author)
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Dopamine D-2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion
- 2019
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In: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 39:3, s. 537-547
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Journal article (peer-reviewed)abstract
- Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA(measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA-BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D-2/3 PET assessment using [C-11] raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D-2/3 receptors to BOLD response in the thalamo-striatalcortical circuit, which supports WM functioning. Critically, the DA-BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA-BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA-BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.
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| 4. |
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| 5. |
- Aapro, Matti, et al.
(author)
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Identifying critical steps towards improved access to innovation in cancer care: a European CanCer Organisation position paper
- 2017
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In: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 82, s. 193-202
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Journal article (peer-reviewed)abstract
- © 2017 In recent decades cancer care has seen improvements in the speed and accuracy of diagnostic procedures; the effectiveness of surgery, radiation therapy and medical treatments; the power of information technology; and the development of multidisciplinary, specialist-led approaches to care. Such innovations are essential if we are to continue improving the lives of cancer patients across Europe despite financial pressures on our healthcare systems. Investment in innovation must be balanced with the need to ensure the sustainability of healthcare budgets, and all health professionals have a responsibility to help achieve this balance. It requires scrutiny of the way care is delivered; we must be ready to discontinue practices or interventions that are inefficient, and prioritise innovations that may deliver the best outcomes possible for patients within the limits of available resources. Decisions on innovations should take into account their long-term impact on patient outcomes and costs, not just their immediate costs. Adopting a culture of innovation requires a multidisciplinary team approach, with the patient at the centre and an integral part of the team. It must take a whole-system and whole-patient perspective on cancer care and be guided by high-quality real-world data, including outcomes relevant to the patient and actual costs of care; this accurately reflects the impact of any innovation in clinical practice. The European CanCer Organisation is committed to working with its member societies, patient organisations and the cancer community at large to find sustainable ways to identify and integrate the most meaningful innovations into all aspects of cancer care.
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| 6. |
- Ahlén Bergman, Emma, et al.
(author)
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Increased CD4+ T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients
- 2018
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In: Clinical Epigenetics. - : BMC. - 1868-7083 .- 1868-7075. ; 10
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4+ T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4+ T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy.RESULTS: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4+ lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4+ lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p < 0.0001, IL13 -11 bp p < 0.05, IL17A -122 bp p < 0.01 and FOXP3 -77 bp p > 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4+ T cells for all four investigated loci, most prominently in IFNG p < 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4+ T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3.CONCLUSION: Increased lineage commitment in CD4+ T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4+ T cell lineages as a useful readout for clinical staging.
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| 7. |
- Alvaeus, Julia, et al.
(author)
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Fewer tumour draining sentinel nodes in patients with progressing muscle invasive bladder cancer, after neoadjuvant chemotherapy and radical cystectomy
- 2020
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In: World journal of urology. - : Springer. - 0724-4983 .- 1433-8726. ; 38, s. 2207-2213
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Journal article (peer-reviewed)abstract
- PURPOSE: To examine the relationship between the number of tumour draining sentinel nodes (SNs) and pathoanatomical outcomes, in muscle-invasive bladder cancer (MIBC), in patients undergoing neoadjuvant chemotherapy (NAC) and radical cystectomy (RC).MATERIALS AND METHODS: In an ongoing prospective multicenter study, we included 230 patients with suspected urothelial MIBC from ten Swedish urological centers. All underwent TURb and clinical staging. From the cohort, 116 patients with urothelial MIBC; cT2-cT4aN0M0, underwent radical cystectomy (RC) and lymphadenectomy with SN-detection (SNd). 83 patients received cisplatin-based NAC and 33 were NAC-naïve. The number and locations of detected SNs and non-SNs were recorded for each patient. The NAC treated patients were categorized by pathoanatomical outcomes post-RC into three groups: complete responders (CR), stable disease (SD) and progressive disease (PD). Selected covariates with possible impact on SN-yield were tested in uni -and multivariate analyses for NAC-treated patients only.RESULTS: In NAC treated patients, the mean number of SNs was significantly higher in CR patients (3.3) and SD patients (3.6) compared with PD patients (1.4) (p = 0.034). In a linear multivariate regression model, the number of harvested nodes was the only independent variable that affected the number of SNs (p = 0.0004).CONCLUSIONS: The number of tumor-draining SNs in NAC-treated patients was significantly lower in patients with progressive disease.
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| 8. |
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| 9. |
- Andersson, Jonas, et al.
(author)
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Association of adipose tissue blood flow with fat depot sizes and adipokines in women
- 2012
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In: International Journal of Obesity. - : Nature Publishing Group. - 0307-0565 .- 1476-5497. ; 36:6, s. 783-789
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Journal article (peer-reviewed)abstract
- Objective: To explore possible associations between adipose tissue (AT) blood flow (ATBF), AT depot sizes and adipocyte-derived hormones (adipokines) in women.Subjects: In all, 43 healthy women were divided into four groups: normal-weight (n=11) and obese (n=11) pre-menopausal women and normal-weight (n=10) and obese (n=11) post-menopausal women.Methods: Fasting levels of adipokines were obtained, and a single-slice computed tomography scan at the level of L4-L5 was used to estimate fat depot sizes. ATBF was assessed by xenon washout while in a fasting state and after oral glucose load. We also measured glucose, insulin and non-esterified fatty acids.Results: Total, subcutaneous and visceral AT areas strongly correlated with ATBF (all P<0.001). Circulating leptin levels strongly and inversely correlated with ATBF (P=0.001), but this association did not remain after adjustment for body mass index. Adiponectin was not associated with blood flow.Conclusion: ATBF is closely linked to subcutaneous and visceral AT size. Further analyses are needed to determine possible mediators of this association, including mechanistic studies to assess a putative role for leptin as a significant modulator of blood flow. International Journal of Obesity advance online publication, 26 July 2011; doi:10.1038/ijo.2011.152.
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| 10. |
- Andersson, Ronny, et al.
(author)
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Effects of interferon-[alpha], verapamil and dacarbazine in the treatment of advanced malignant melanoma
- 2003
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In: Melanoma research. - 0960-8931 .- 1473-5636. ; 13:1, s. 87-91
-
Journal article (peer-reviewed)abstract
- Treatment of patients with metastatic melanoma with either dacarbazine (DTIC) or interferon-[alpha] (IFN[alpha]) as single drugs, or in combination, results in a response rate of approximately 15–20%. This study evaluated the activity and toxicity following treatment with a combination of DTIC, IFN[alpha]2b and verapamil (VPL). Thirty patients with disseminated metastatic melanoma received DTIC 250 mg/m2 on days 1–5 of a 4 week schedule, IFN[alpha]2b 3 MIU on days 1–5 each week, and VPL 80 mg three times a day throughout the cycle, until either disease progression or serious toxicity was observed. Among the 28 evaluable patients, there were four complete responses (CRs), five partial responses (PRs) and eight patients with stable disease (SD). The overall response rate (CR + PR) was 32%. Two patients with a CR were long-term survivors (45 and 34 months) and a third is still in complete remission after 49 months. The fourth CR patient relapsed and died with progressive brain metastases after 8 months. Among the eight patients with SD, one survived for 22 months and another for 34 months. Despite one toxic death, these results suggest that this treatment regimen is well tolerated and seems to be more effective than DTIC alone in a subset of patients. A controlled randomized study would be required to determine the value of adding VPL and IFN[alpha]2b to DTIC.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Bailey, D. L., et al.
(author)
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Combined PET/MRI : Global Warming-Summary Report of the 6th International Workshop on PET/MRI, March 27-29, 2017, Tubingen, Germany
- 2018
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In: Molecular Imaging and Biology. - : SPRINGER. - 1536-1632 .- 1860-2002. ; 20:1, s. 4-20
-
Research review (peer-reviewed)abstract
- The 6th annual meeting to address key issues in positron emission tomography (PET)/magnetic resonance imaging (MRI) was held again in Tubingen, Germany, from March 27 to 29, 2017. Over three days of invited plenary lectures, round table discussions and dialogue board deliberations, participants critically assessed the current state of PET/MRI, both clinically and as a research tool, and attempted to chart future directions. The meeting addressed the use of PET/MRI and workflows in oncology, neurosciences, infection, inflammation and chronic pain syndromes, as well as deeper discussions about how best to characterise the tumour microenvironment, optimise the complementary information available from PET and MRI, and how advanced data mining and bioinformatics, as well as information from liquid biomarkers (circulating tumour cells and nucleic acids) and pathology, can be integrated to give a more complete characterisation of disease phenotype. Some issues that have dominated previous meetings, such as the accuracy of MR-based attenuation correction (AC) of the PET scan, were finally put to rest as having been adequately addressed for the majority of clinical situations. Likewise, the ability to standardise PET systems for use in multicentre trials was confirmed, thus removing a perceived barrier to larger clinical imaging trials. The meeting openly questioned whether PET/MRI should, in all cases, be used as a whole-body imaging modality or whether in many circumstances it would best be employed to give an in-depth study of previously identified disease in a single organ or region. The meeting concluded that there is still much work to be done in the integration of data from different fields and in developing a common language for all stakeholders involved. In addition, the participants advocated joint training and education for individuals who engage in routine PET/MRI. It was agreed that PET/MRI can enhance our understanding of normal and disrupted biology, and we are in a position to describe the in vivo nature of disease processes, metabolism, evolution of cancer and the monitoring of response to pharmacological interventions and therapies. As such, PET/MRI is a key to advancing medicine and patient care.
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| 16. |
- Bailey, D. L., et al.
(author)
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Combined PET/MRI : from Status Quo to Status Go. Summary Report of the Fifth International Workshop on PET/MR Imaging; February 15-19, 2016; Tubingen, Germany
- 2016
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In: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 18:5, s. 637-650
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Journal article (peer-reviewed)abstract
- This article provides a collaborative perspective of the discussions and conclusions from the fifth international workshop of combined positron emission tomorgraphy (PET)/magnetic resonance imaging (MRI) that was held in Tubingen, Germany, from February 15 to 19, 2016. Specifically, we summarise the second part of the workshop made up of invited presentations from active researchers in the field of PET/MRI and associated fields augmented by round table discussions and dialogue boards with specific topics. This year, this included practical advice as to possible approaches to moving PET/MRI into clinical routine, the use of PET/MRI in brain receptor imaging, in assessing cardiovascular diseases, cancer, infection, and inflammatory diseases. To address perceived challenges still remaining to innovatively integrate PET and MRI system technologies, a dedicated round table session brought together key representatives from industry and academia who were engaged with either the conceptualisation or early adoption of hybrid PET/MRI systems. Discussions during the workshop highlighted that emerging unique applications of PET/MRI such as the ability to provide multi-parametric quantitative and visual information which will enable not only overall disease detection but also disease characterisation would eventually be regarded as compelling arguments for the adoption of PET/MR. However, as indicated by previous workshops, evidence in favour of this observation is only growing slowly, mainly due to the ongoing inability to pool data cohorts from independent trials as well as different systems and sites. The participants emphasised that moving from status quo to status go entails the need to adopt standardised imaging procedures and the readiness to act together prospectively across multiple PET/MRI sites and vendors.
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| 17. |
- Bergdahl, Jan, et al.
(author)
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Treatment of chronic stress in employees: Subjective, cognitive, and neural correlates.
- 2005
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In: Scandinavian Journal of Psychology. - : Wiley. - 0036-5564 .- 1467-9450. ; 46:5, s. 395-402
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Journal article (peer-reviewed)abstract
- This study reports the effect of an affect-focused intervention program, the Affect School (AS), on stress, psychological symptoms, cognitive functioning and neural activity. Fifty employees in social service and education, with high levels of chronic stress, were randomly divided into a treatment (N=27) and control (N=23) group. Complete sets of data were available in 20 participants in the treatment group and in 17 in the control group. The Percieved Stress Questionnaire assessed stress and the Symptom Chech List-90 psychological symptoms before and after the treatment. Episodic-memory functioning under focussed and divided attention conditions was also assessed. Prior and after the AS, seven participants in the treatment group were studied with fMRI during episodic memory processing. After the AS there was a reduction in stress and psychological symptoms for the treatment group but not in the control group. The controls showed a reduction in episodic memory functioning whereas the performance of the treatment group remained intact. The fMRI scanning indicated a qualitative change in the neural network subserving episodic memory. These preliminary results suggest that the AS is effective on individuals with high stress.
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| 18. |
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| 19. |
- Björeland, Ulrika, et al.
(author)
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Impact of neoadjuvant androgen deprivation therapy on magnetic resonance imaging features in prostate cancer before radiotherapy
- 2021
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In: Physics and Imaging in Radiation Oncology. - : Elsevier. - 2405-6316. ; 17, s. 117-123
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Journal article (peer-reviewed)abstract
- Background and purpose: In locally advanced prostate cancer (PC), androgen deprivation therapy (ADT) in combination with whole prostate radiotherapy (RT) is the standard treatment. ADT affects the prostate as well as the tumour on multiparametric magnetic resonance imaging (MRI) with decreased PC conspicuity and impaired localisation of the prostate lesion. Image texture analysis has been suggested to be of aid in separating tumour from normal tissue. The aim of the study was to investigate the impact of ADT on baseline defined MRI features in prostate cancer with the goal to investigate if it might be of use in radiotherapy planning.Materials and methods: Fifty PC patients were included. Multiparametric MRI was performed before, and three months after ADT. At baseline, a tumour volume was delineated on apparent diffusion coefficient (ADC) maps with suspected tumour content and a reference volume in normal prostatic tissue. These volumes were transferred to MRIs after ADT and were analysed with first-order -and invariant Haralick -features.Results: At baseline, the median value and several of the invariant Haralick features of ADC, showed a significant difference between tumour and reference volumes. After ADT, only ADC median value could significantly differentiate the two volumes.Conclusions: Invariant Haralick -features could not distinguish between baseline MRI defined PC and normal tissue after ADT. First-order median value remained significantly different in tumour and reference volumes after ADT, but the difference was less pronounced than before ADT.
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| 20. |
- Brolin, Gustav, et al.
(author)
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The accuracy of quantitative parameters in Tc-99m-MAG3 dynamic renography : a national audit based on virtual image data
- 2016
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In: Clinical Physiology and Functional Imaging. - : Wiley. - 1475-0961 .- 1475-097X. ; 36:2, s. 146-154
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Journal article (peer-reviewed)abstract
- Assessment of image analysis methods and computer software used in Tc-99m-MAG3 dynamic renography is important to ensure reliable study results and ultimately the best possible care for patients. In this work, we present a national multicentre study of the quantification accuracy in Tc-99m-MAG3 renography, utilizing virtual dynamic scintigraphic data obtained by Monte Carlo-simulated scintillation camera imaging of digital phantoms with time-varying activity distributions. Three digital phantom studies were distributed to the participating departments, and quantitative evaluation was performed with standard clinical software according to local routines. The differential renal function (DRF) and time to maximum renal activity (T-max) were reported by 21 of the 28 Swedish departments performing Tc-99m-MAG3 studies as of 2012. The reported DRF estimates showed a significantly lower precision for the phantom with impaired renal uptake than for the phantom with normal uptake. The T-max estimates showed a similar trend, but the difference was only significant for the right kidney. There was a significant bias in the measured DRF for all phantoms caused by different positions of the left and right kidney in the anterior-posterior direction. In conclusion, this study shows that virtual scintigraphic studies are applicable for quality assurance and that there is a considerable uncertainty associated with standard quantitative parameters in dynamic Tc-99m-MAG3 renography, especially for patients with impaired renal function.
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| 21. |
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| 22. |
- Bäckström, David C, M.D. 1978-, et al.
(author)
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NfL as a biomarker for neurodegeneration and survival in Parkinson disease
- 2020
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In: Neurology. - : Wolters Kluwer. - 0028-3878 .- 1526-632X. ; 95:7, s. e827-e838
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To determine whether neurofilament light chain protein in CSF (cNfL), a sensitive biomarker of neuroaxonal damage, reflects disease severity or can predict survival in Parkinson disease (PD).METHODS: We investigated whether disease severity, phenotype, or survival in patients with new-onset PD correlates with cNfL concentrations around the time of diagnosis in the population-based New Parkinsonism in Umeå (NYPUM) study cohort (n = 99). A second, larger new-onset PD cohort (n = 194) was used for independent validation. Association of brain pathology with the cNfL concentration was examined with striatal dopamine transporter imaging and repeated diffusion tensor imaging at baseline and 1 and 3 years.RESULTS: Higher cNfL in the early phase of PD was associated with greater severity of all cardinal motor symptoms except tremor in both cohorts and with shorter survival and impaired olfaction. cNfL concentrations above the median of 903 ng/L conferred an overall 5.8 times increased hazard of death during follow-up. After adjustment for age and sex, higher cNfL correlated with striatal dopamine transporter uptake deficits and lower fractional anisotropy in diffusion tensor imaging of several axonal tracts.CONCLUSIONS: cNfL shows usefulness as a biomarker of disease severity and to predict survival in PD. The present results indicate that the cNfL concentration reflects the intensity of the neurodegenerative process, which could be important in future clinical trials.CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with PD, cNfL concentrations are associated with more severe disease and shorter survival.
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| 23. |
- Bäckström, David C, M.D. 1978-, et al.
(author)
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Prediction and early biomarkers of cognitive decline in Parkinson disease and atypical parkinsonism: a population-based study
- 2022
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In: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:2
-
Journal article (peer-reviewed)abstract
- Backstrom et al. report that, in a population-based cohort of patients with new-onset Parkinson disease, approximately half develop dementia within 10 years. Measurement of CSF biomarkers together with baseline cognitive function, olfaction and motor disease severity has high accuracy for predicting who will develop dementia. The progression of cognitive decline is heterogeneous in the three most common idiopathic parkinsonian diseases: Parkinson disease, multiple system atrophy and progressive supranuclear palsy. The causes for this heterogeneity are not fully understood, and there are no validated biomarkers that can accurately identify patients who will develop dementia and when. In this population-based, prospective study, comprehensive neuropsychological testing was performed repeatedly in new-onset, idiopathic parkinsonism. Dementia was diagnosed until 10 years and participants (N = 210) were deeply phenotyped by multimodal clinical, biochemical, genetic and brain imaging measures. At baseline, before the start of dopaminergic treatment, mild cognitive impairment was prevalent in 43.4% of the patients with Parkinson disease, 23.1% of the patients with multiple system atrophy and 77.8% of the patients with progressive supranuclear palsy. Longitudinally, all three diseases had a higher incidence of cognitive decline compared with healthy controls, but the types and severity of cognitive dysfunctions differed. In Parkinson disease, psychomotor speed and attention showed signs of improvement after dopaminergic treatment, while no such improvement was seen in other diseases. The 10-year cumulative probability of dementia was 54% in Parkinson disease and 71% in progressive supranuclear palsy, while there were no cases of dementia in multiple system atrophy. An easy-to-use, multivariable model that predicts the risk of dementia in Parkinson disease within 10 years with high accuracy (area under the curve: 0.86, P < 0.001) was developed. The optimized model adds CSF biomarkers to four easily measurable clinical features at baseline (mild cognitive impairment, olfactory function, motor disease severity and age). The model demonstrates a highly variable but predictable risk of dementia in Parkinson disease, e.g. a 9% risk within 10 years in a patient with normal cognition and CSF amyloid-beta(42) in the highest tertile, compared with an 85% risk in a patient with mild cognitive impairment and CSF amyloid-beta(42) in the lowest tertile. Only small or no associations with cognitive decline were found for factors that could be easily modifiable (such as thyroid dysfunction). Risk factors for cognitive decline in multiple system atrophy and progressive supranuclear palsy included signs of systemic inflammation and eye movement abnormalities. The predictive model has high accuracy in Parkinson disease and might be used for the selection of patients into clinical trials or as an aid to improve the prevention of dementia.
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| 24. |
- Bäckström, David, et al.
(author)
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Early predictors of mortality in parkinsonism and Parkinson disease: A population-based study
- 2018
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In: Neurology. - : Wolters Kluwer. - 1526-632X .- 0028-3878. ; 91:22
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To examine mortality and associated risk factors, including possible effects of mild cognitive impairment, imaging, and CSF abnormalities, in a community-based population with incident parkinsonism and Parkinson disease. METHODS: One hundred eighty-two patients with new-onset, idiopathic parkinsonism were diagnosed from January 2004 through April 2009, in a catchment area of 142,000 inhabitants in Sweden. Patients were comprehensively investigated according to a multimodal research protocol and followed prospectively for up to 13.5 years. A total of 109 patients died. Mortality rates in the general Swedish population were used to calculate standardized mortality ratio and expected survival, and Cox proportional hazard models were used to investigate independent predictors of mortality. RESULTS: The standardized mortality ratio for all patients was 1.84 (95% confidence interval 1.50-2.22, p < 0.001). Patients with atypical parkinsonism (multiple system atrophy or progressive supranuclear palsy) had the highest mortality. In early Parkinson disease, a mild cognitive impairment diagnosis, freezing of gait, hyposmia, reduced dopamine transporter activity in the caudate, and elevated leukocytes in the CSF were significantly associated with shorter survival. CONCLUSION: Although patients presenting with idiopathic parkinsonism have reduced survival, the survival is highly dependent on the type and characteristics of the parkinsonian disorder. Patients with Parkinson disease presenting with normal cognitive function seem to have a largely normal life expectancy. The finding of a subtle CSF leukocytosis in patients with Parkinson disease with short survival may have clinical implications. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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| 25. |
- de Boer, Lieke, et al.
(author)
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Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age
- 2017
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In: eLIFE. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 6
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Journal article (peer-reviewed)abstract
- Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability.
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| 26. |
- de Boer, Lieke, et al.
(author)
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Corticostriatal White Matter Integrity and Dopamine D1 Receptor Availability Predict Age Differences in Prefrontal Value Signaling during Reward Learning
- 2020
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In: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 30:10, s. 5270-5280
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Journal article (peer-reviewed)abstract
- Probabilistic reward learning reflects the ability to adapt choices based on probabilistic feedback. The dopaminergically innervated corticostriatal circuit in the brain plays an important role in supporting successful probabilistic reward learning. Several components of the corticostriatal circuit deteriorate with age, as it does probabilistic reward learning. We showed previously that D1 receptor availability in NAcc predicts the strength of anticipatory value signaling in vmPFC, a neural correlate of probabilistic learning that is attenuated in older participants and predicts probabilistic reward learning performance. We investigated how white matter integrity in the pathway between nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC) relates to the strength of anticipatory value signaling in vmPFC in younger and older participants. We found that in a sample of 22 old and 23 young participants, fractional anisotropy in the pathway between NAcc and vmPFC predicted the strength of value signaling in vmPFC independently from D1 receptor availability in NAcc. These findings provide tentative evidence that integrity in the dopaminergic and white matter pathways of corticostriatal circuitry supports the expression of value signaling in vmPFC which supports reward learning, however, the limited sample size calls for independent replication. These and future findings could add to the improved understanding of how corticostriatal integrity contributes to reward learning ability.
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| 27. |
- de Boer, Lieke, et al.
(author)
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Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning
- 2019
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:1, s. 261-270
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Journal article (peer-reviewed)abstract
- Learning to act to obtain reward and inhibit to avoid punishment is easier compared with learning the opposite contingencies. This coupling of action and valence is often thought of as a Pavlovian bias, although recent research has shown it may also emerge through instrumental mechanisms. We measured this learning bias with a rewarded go/no-go task in 60 adults of different ages. Using computational modeling, we characterized the bias as being instrumental. To assess the role of endogenous dopamine (DA) in the expression of this bias, we quantified DA D1 receptor availability using positron emission tomography (PET) with the radioligand [11C]SCH23390. Using principal-component analysis on the binding potentials in a number of cortical and striatal regions of interest, we demonstrated that cortical, dorsal striatal, and ventral striatal areas provide independent sources of variance in DA D1 receptor availability. Interindividual variation in the dorsal striatal component was related to the strength of the instrumental bias during learning. These data suggest at least three anatomical sources of variance in DA D1 receptor availability separable using PET in humans, and we provide evidence that human dorsal striatal DA D1 receptors are involved in the modulation of instrumental learning biases.
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| 28. |
- Ekman, Urban, et al.
(author)
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Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment : a cross-sectional study
- 2012
-
In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 11:8, s. 679-687
-
Journal article (peer-reviewed)abstract
- Background: Many patients with Parkinson's disease have mild cognitive impairment (MCI). Deficits in executive functions and working memory suggest dysfunctional frontostriatal brain circuitry. We aimed to assess brain responses during a working memory task in a cohort of newly diagnosed drug-naive patients with Parkinson's disease with and without MCI.Methods: Participants were recruited within a prospective cohort study of incident patients with idiopathic parkinsonism, including Parkinson's disease. Between Jan 1, 2004, and April 30, 2009, all physicians in the Umea catchment area were requested to refer all individuals with suspected parkinsonism to the Department of Neurology at lima University. Included patients fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease. Control individuals were matched on the basis of age and sex with the first 50 patients included in the study. Participants who scored 1.5 SDs or more below the population mean on at least two cognitive measures were diagnosed with MCI. The primary outcome measures were functional MRI blood-oxygen-level-dependent signal and SPECT presynaptic uptake. Functional MRI was done during a verbal two-back working memory task. Presynaptic dopamine SPECT was done to assess presynaptic striatal dopaminergic system integrity. Event-related transient analyses of functional MRI data were done for the whole brain and for frontostriatal regions of interest, and semi-quantitative SPECT analyses were done for striatal regions of interest.Findings: Compared with controls (n=24), patients with Parkinson's disease (n=77) had under-recruitment in an extensive brain network including bilateral striatal and frontal regions (p<0.001). Within the Parkinson's disease group, patients with Parkinson's disease and MCI (n=30) had additional under-recruitment in the right dorsal caudate nucleus (p=0.005) and the bilateral anterior cingulate cortex (p<0.001) compared with patients with Parkinson's disease without MCI (n=26). In patients with Parkinson's disease and MCI, SPECT uptake in the right caudate was lower than in patients with Parkinson's disease without MCI (p=0.008) and correlated with striatal functional MRI blood-oxygen-level-dependent signal (r=0.32, p=0.031).Interpretation: These altered brain responses in patients with Parkinson's disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction.
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| 29. |
- Elgh, Eva, et al.
(author)
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Memory functions and rCBF (99m)Tc-HMPAO SPET : developing diagnostics in Alzheimer's disease
- 2002
-
In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 29:9, s. 1140-1148
-
Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is a primary degenerative disease of the brain. The prevalence increases with age, with devastating consequences for the individual and society. The aim of this study was to evaluate whether patients with early AD show an altered regional cerebral blood flow (rCBF) compared with control persons. Furthermore, we aimed to investigate the correlation between rCBF in sublobar volumes of the brain and performance on memory tests. Memory tests were chosen to evaluate episodic and semantic memory. Fourteen patients (aged 75.2+/-8.8 years) with early AD and 15 control persons (aged 71.4+/-3.2 years) were included. rCBF measurements with single-photon emission tomography (SPET) using technetium-99m hexamethylpropylene amine oxime (HMPAO) were performed. The rCBF (99m)Tc-HMPAO SPET images were spatially transformed to fit a brain atlas and normalised for differences in rCBF (Computerised Brain Atlas software). Cortical and subcortical volumes of interest (VOIs) were analysed and compared. Compared with the controls, AD patients showed a significantly lower rCBF ratio in temporoparietal regions, including the left hippocampus. The diagnostic sensitivity and specificity for AD were high in temporoparietal regions. AD patients had significantly reduced performance on semantic and, in particular, episodic memory tests compared with age-matched normative data, and their performance on several episodic tests correlated with rCBF ratios in parietal and temporal regions, including the left hippocampus. The correlation between rCBF ratio and level of episodic memory performance suggests that abnormalities in rCBF pattern underlie impaired episodic memory functioning in AD.
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| 30. |
- Eriksson, David, et al.
(author)
-
Apoptotic signalling in HeLa Hep2 cells following 5 Gy of cobalt-60 gamma radiation
- 2009
-
In: Anticancer Research. - 0250-7005 .- 1791-7530. ; 29:11, s. 4361-4366
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The apoptotic signalling pathways involved in the delayed type of apoptosis occurring in HeLa Hep2 cells following radiation were investigated. MATERIALS AND METHODS: HeLa Hep2 cells were exposed to 5 Gy of cobalt-60 radiation. The activation of caspase-2, caspase-8, caspase-9 and effector caspase-3 was investigated by caspase assay plates and Western blots. Cleavage of poly (ADP-ribose) polymerase (PARP) was analysed on Western blots. HeLa Hep2 cells were irradiated with or without preincubation with inhibitors of protein synthesis (cycloheximide, CHX) and caspases, followed by TUNEL staining and caspase assay plate evaluation. RESULTS: Initiator caspases-2, -8, -9, and effector caspase-3, were found to be activated and PARP cleaved following irradiation. CHX completely inhibited the caspase activation and the associated apoptosis. Pretreatment with caspase-2 inhibitor indicated that caspase-2 was involved in the execution of the apoptosis. CONCLUSION: Activation of the apoptotic signalling pathways following irradiation of HeLa Hep2 cells includes components from the intrinsic as well as the extrinsic pathways and seems to require de novo protein synthesis.
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| 31. |
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| 32. |
- Eriksson, David, et al.
(author)
-
Cell cycle disturbances and mitotic catastrophes in HeLa Hep2 cells following 2.5 to 10 Gy of ionizing radiation.
- 2007
-
In: Clin Cancer Res. - 1078-0432. ; 13:18 Pt 2, s. 5501s-5508s
-
Journal article (peer-reviewed)abstract
- PURPOSE: Experimental radioimmunotherapy delivering absorbed doses of 2.5 to 10 Gy has been shown to cause growth retardation of tumors. The purpose of this study was to elucidate the sequential molecular and cellular events occurring in HeLa Hep2 cells exposed to such doses. METHODS: Dose-response curves, activation of cell cycle checkpoints, and mitotic behavior were investigated in HeLa Hep2 cells following 2.5- to 10-Gy irradiation by carrying out 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, Western blots, fluorescence-activated cell sorting analysis, and immunofluorescence stainings. Terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining was used to detect apoptosis. RESULTS: A G2-M arrest was shown by fluorescence-activated cell sorting analysis. p53 and p21 were found to be up-regulated but were not immediately related to the arrest. The G2-M arrest was transient and the cells reentered the cell cycle still containing unrepaired cellular damage. This premature entry caused an increase of anaphase bridges, lagging chromosomal material, and multipolar mitotic spindles as visualized by propidium iodide staining and immunofluorescence staining with alpha-tubulin and gamma-tubulin antibodies. Furthermore, a dose-dependent significant increase in centrosome numbers from 12.6+/-6.6% to 67+/-5.3% was identified as well as a dose-dependent increase of polyploid cells from 2.8+/-1.3% to 17.6+/-2.1% with the highest absorbed dose of 10 Gy. These disturbances caused the cells to progress into mitotic catastrophe and a fraction of these dying cells showed apoptotic features as displayed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining 5 to 7 days after irradiation. CONCLUSION: An absorbed dose of 2.5 to 10 Gy was shown to force HeLa Hep2 cells into mitotic catastrophe and delayed apoptosis. These might be important cell death mechanisms involved in tumor growth retardation following radioimmunotherapy of solid tumors.
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| 33. |
- Eriksson, David, et al.
(author)
-
Combined low dose radio- and radioimmunotherapy of experimental HeLa Hep 2 tumours.
- 2003
-
In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 30:6, s. 895-906
-
Journal article (peer-reviewed)abstract
- Radiation therapy of malignant tumours can be delivered by external beam radiation (RT) or radioimmunotherapy (RIT), using nuclides attached to monoclonal antibodies (mAbs). These treatment modalities have now been combined in order to investigate putative therapeutic advantages and elucidate the biological responses involved. Nude mice were transplanted subcutaneously on the back with human HeLa Hep2 tumour cells. RT (3x5 Gy) and/or 100 microg (131)I-labelled mAb H7, against placental alkaline phosphatase, or (131)I-labelled mAb TS1, against cytokeratin, was administered separately or in combination (specific activity of 120-200 MBq/mg antibody). Significant tumour growth retardation was observed both with RT alone and with RIT alone. Combining these regimens enhanced the therapeutic effects further, and a significant reduction in tumour volume could be demonstrated. The tumours were subjected to extensive histochemical and immunohistochemical investigations in order to elucidate changes in biology and histology within them. The following stainings were used: haematoxylin-eosin (morphology), Ki67 (proliferation), M30 (apoptosis), TUNEL (apoptosis) and endoglin (vascularisation). Tumours in the control group grew fast, with an average tumour doubling time of 9 days. These tumours contained large viable tumour cell masses displaying vast proliferation zones of Ki67-positive tumour cells, as well as necrotic regions and small amounts of connective tissue. Apoptotic cells could be identified both with M30 and TUNEL staining. When RT was applied, the growth rate was significantly reduced (doubling time 19 days) and typical alterations in morphology were seen, with a relative increase in connective tissue and a decrease in necrotic regions. Apoptotic cells were identified and a decrease in cell density was also observed. When RIT alone was applied, the growth parameters indicated a longer lasting growth reduction, especially when TS1 was used separately or in combination with H7. The histological appearances of these tumours were somewhat different from the RT-treated tumours, with a larger portion of intratumoural cysts. These tumours also presented a reduced tumour cell density. Dramatic effects were observed when RT was combined with RIT, with a pronounced growth reduction seen in all combination treatment groups. Pronounced tumour volume reduction was also evident in both the RT + RIT ((131)I-TS1) group and RT + RIT ((131)I-TS1/(131)I-H7) group, and in some animals no tumour remained at all. The morphology of the tumour remnants at day 22 was chaotic with a drastically changed histology, with presence of abundant cysts, low fractions of Ki67-positive cells, reduction in cell density, increased amounts of connective tissue and a decrease in necrotic regions. Again, apoptotic cells could be identified, scattered throughout the viable regions. Combining RT and RIT seems to generate an efficient treatment with convincing and long-lasting tumour growth inhibition, which is reflected in a highly aberrant histology within the tumour. Results obtained in this study indicate that both necrosis and apoptosis may be involved in the process leading to this efficient therapy of epithelially derived tumours.
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| 34. |
- Eriksson, David, et al.
(author)
-
Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells
- 2008
-
In: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 23:5, s. 541-549
-
Journal article (peer-reviewed)abstract
- Iodine-131 (131I) has been used both in unconjugated form and conjugated to antibody derivates (i.e., radioimmunotherapy; RIT) to treat malignant diseases. The mechanisms by which 131I-irradiation causes growth retardation are, however, inadequately understood. The aim of this study was to elucidate the sequential molecular and cellular events that initiate cell death in HeLa Hep2 cells exposed to 131I. In this paper, HeLa Hep2 cells were found to display a transient G2-M arrest following irradiation, but then reentered the cell cycle still containing unrepaired cellular damage. An increase of multipolar mitotic spindles, as well as a significant increase in centrosome numbers from 8.8% +/- 1.9% in controls to 54.7% +/- 2.2% in irradiated cells, was observed (p < 0.0001). A subsequent failure of cytokinesis caused the cells to progress into mitotic catastrophe. This was accompanied by the formation of giant cells with multiple nuclei, multilobulated nuclei, and an increased frequency of polyploidy cells. A fraction of the cells also displayed apoptotic features, including the activation of initiator caspases-2, -8, -9, and effector caspase-3, as well as cleavage of poly(ADP-ribose) polymerase, a cell-death substrate for active caspase-3. These findings demonstrate that mitotic catastrophes and the activation of a delayed type of apoptosis might be important mechanisms involved in cell death following the RIT of solid tumors with -emitting radionuclides, such as 131I.
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| 35. |
- Eriksson, Johan, et al.
(author)
-
Similar frontal and distinct posterior cortical regions mediate visual and auditory perceptual awareness
- 2007
-
In: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 17:4, s. 760-765
-
Journal article (peer-reviewed)abstract
- Activity in ventral visual cortex is a consistent neural correlate of visual consciousness. However, activity in this area seems insufficient to produce awareness without additional involvement of frontoparietal regions. To test the generality of the frontoparietal response, neural correlates of auditory awareness were investigated in a paradigm that previously has revealed frontoparietal activity during conscious visual perception. A within-experiment comparison showed that frontal regions were related to both visual and auditory awareness, whereas parietal activity was correlated with visual awareness and superior temporal activity with auditory awareness. These results indicate that frontal regions interact with specific posterior regions to produce awareness in different sensory modalities.
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| 36. |
- Eriksson, Johan, et al.
(author)
-
Visual consciousness : dissociating the neural correlates of perceptual transitions from sustained perception with fMRI
- 2004
-
In: Consciousness and Cognition. - San Diego, Calif. : Academic Press. - 1053-8100 .- 1090-2376. ; 13:1, s. 61-72
-
Journal article (peer-reviewed)abstract
- To investigate the possible dichotomy between the neurophysiological bases of perceptual transitions versus sustaining a particular percept over time, an fMRI study was conducted with subjects viewing fragmented pictures. Unlike most other perceptually unstable stimuli, fragmented pictures give rise to only one perceptual transition and a continuous period of sustained perception. Earlier research is inconclusive on the subject of which anatomical regions should be attributed to what temporal aspect of perception, and the aim of the present study was to shed more light on the subject. In this study occipitotemporal and fronto-parietal regions were found to be activated for both aspects. However, regions in the medial-temporal lobe were activated specifically for transitions, whereas medial and dorsolateral prefrontal regions were activated specifically for sustained perception. These results provide further support for the theory that the initial creation of perceptual awareness and upholding perceptual awareness over time are separate processes involving different brain regions.
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| 37. |
- Erlandsson, Ann, et al.
(author)
-
In vivo clearing of idiotypic antibodies with antiidiotypic antibodies and their derivatives
- 2006
-
In: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 43:6, s. 599-606
-
Journal article (peer-reviewed)abstract
- At immunolocalization of experimental tumors, idiotypic monoclonal antibodies, such as TS1 against cytokeratin 8, can be used to carry and deposit in vivo terapeutics in the tumor. These carriers also remain in the circulation and may cause negative side-effects in other tissues. In this report, several derivatives of the antiidiotypic antibody alphaTS1 were produced and tested for their clearing capacity of the idiotypic carrier antibody TS1. Intact monoclonal alphaTS1, scFv of a alphaTS1 and alphaTS1 Fab'2 and fragments were produced by recombinant technology or by cleavage with Ficin. The scFv was tailored by use of the variable domain genes of the light and heavy chain from the hybridoma clone in combination with a (Gly4Ser)3-linker, followed by expression in E. coli. When tested for clearing capacity, the intact divalent antiidiotypic IgG was found to be the most efficient. The divalent and the monovalent Fab fragment also demonstrated significant clearing, but lower than the intact antiidiotypic IgG. The alphaTS1 scFv antibody when injected separately was not found to clear the idiotype, but could do so when preincubated with the idiotype. Rapid excretion and in vivo instability of this low molecular weight antibody fragment may be the major reasons. Similar results were obtained when the system was reversed and the 131I-labeled antiidiotype IgG was cleared with the idiotype fragment. It is concluded that both intact antiidiotypic IgG, and Fab'2 fragments are able to clear the idiotypic antibodies. The experimental data support the conclusion that the Fc parts from both the idiotype and the antiidiotype may contribute to this elimination.
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| 38. |
- Farnsworth von Cederwald, Bryn, et al.
(author)
-
White matter lesion load determines exercise-induced dopaminergic plasticity and working memory gains in aging
- 2023
-
In: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 13:1
-
Journal article (peer-reviewed)abstract
- Age-related dopamine reductions have been suggested to contribute to maladaptive working memory (WM) function in older ages. One promising intervention approach is to increase physical activity, as this has been associated with plasticity of the striatal dopamine system and WM improvements, however with individual differences in efficacy. The present work focused on the impact of individual differences in white-matter lesion burden upon dopamine D2-like receptor (DRD2) availability and WM changes in response to a 6 months physical activity intervention. While the intervention altered striatal DRD2 availability and WM performance in individuals with no or only mild lesions (p < 0.05), no such effects were found in individuals with moderate-to-severe lesion severity (p > 0.05). Follow-up analyses revealed a similar pattern for processing speed, but not for episodic memory performance. Linear analyses further revealed that lesion volume (ml) at baseline was associated with reduced DRD2 availability (r = −0.41, p < 0.05), and level of DRD2 change (r = 0.40, p < 0.05). Taken together, this study underlines the necessity to consider cerebrovascular health in interventions with neurocognitive targets. Future work should assess whether these findings extend beyond measures of DRD2 availability and WM.
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| 39. |
- Flodin, Pär, 1982-, et al.
(author)
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Does Aerobic Exercise Influence Intrinsic Brain Activity? An Aerobic Exercise Intervention among Healthy Old Adults
- 2017
-
In: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 9
-
Journal article (peer-reviewed)abstract
- Previous studies have indicated that aerobic exercise could reduce age related decline in cognition and brain functioning. Here we investigated the effects of aerobic exercise on intrinsic brain activity. Sixty sedentary healthy males and females (64–78 years) were randomized into either an aerobic exercise group or an active control group. Both groups recieved supervised training, 3 days a week for 6 months. Multimodal brain imaging data was acquired before and after the intervention, including 10 min of resting state brain functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL). Additionally, a comprehensive battery of cognitive tasks assessing, e.g., executive function and episodic memory was administered. Both the aerobic and the control group improved in aerobic capacity (VO2-peak) over 6 months, but a significant group by time interaction confirmed that the aerobic group improved more. Contrary to our hypothesis, we did not observe any significant group by time interactions with regard to any measure of intrinsic activity. To further probe putative relationships between fitness and brain activity, we performed post hoc analyses disregarding group belongings. At baseline, VO2-peak was negativly related to BOLD-signal fluctuations (BOLDSTD) in mid temporal areas. Over 6 months, improvements in aerobic capacity were associated with decreased connectivity between left hippocampus and contralateral precentral gyrus, and positively to connectivity between right mid-temporal areas and frontal and parietal regions. Independent component analysis identified a VO2-related increase in coupling between the default mode network and left orbitofrontal cortex, as well as a decreased connectivity between the sensorimotor network and thalamus. Extensive exploratory data analyses of global efficiency, connectome wide multivariate pattern analysis (connectome-MVPA), as well as ASL, did not reveal any relationships between aerobic fitness and intrinsic brain activity. Moreover, fitness-predicted changes in functional connectivity did not relate to changes in cognition, which is likely due to absent cross- sectional or longitudinal relationships between VO2-peak and cognition. We conclude that the aerobic exercise intervention had limited influence on patterns of intrinsic brain activity, although post hoc analyses indicated that individual changes in aerobic capacity preferentially influenced mid-temporal brain areas.
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| 40. |
- Garzón, Benjamín, et al.
(author)
-
Role of dopamine and gray matter density in aging effects and individual differences of functional connectomes
- 2021
-
In: Brain Structure and Function. - : Springer Science and Business Media LLC. - 1863-2653 .- 1863-2661. ; 226, s. 743-758
-
Journal article (peer-reviewed)abstract
- With increasing age, functional connectomes become dissimilar across normal individuals, reflecting heterogenous aging effects on functional connectivity (FC). We investigated the distribution of these effects across the connectome and their relationship with age-related differences in dopamine (DA) D1 receptor availability and gray matter density (GMD). With this aim, we determined aging effects on mean and interindividual variance of FC using fMRI in 30 younger and 30 older healthy subjects and mapped the contribution of each connection to the patterns of age-related similarity loss. Aging effects on mean FC accounted mainly for the dissimilarity between connectomes of younger and older adults, and were related, across brain regions, to aging effects on DA D1 receptor availability. Aging effects on the variance of FC indicated a global increase in variance with advancing age, explained connectome dissimilarity among older subjects and were related to aging effects on variance of GMD. The relationship between aging and the similarity of connectomes can thus be partly explained by age differences in DA modulation and gray matter structure.
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| 41. |
- Gatidis, Sergios, et al.
(author)
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State of affairs of hybrid imaging in Europe : two multi-national surveys from 2017
- 2019
-
In: Insights into Imaging. - : Springer. - 1869-4101. ; 10:1
-
Journal article (peer-reviewed)abstract
- Objectives: To assess the current state of hybrid imaging in Europe with respect to operations, reading and reporting, as well as qualification and training.Methods: The first survey (LOCAL) was sent to the heads of the departments of radiology and nuclear medicine in Europe in 2017, including 15 questions regarding the organisation of hybrid imaging operations, reporting strategies for PET/CT and the existence of relevant training programmes. The second survey (NATIONAL) consisted of 10 questions and was directed to the national ministries of health of 37 European countries addressing combined training options in radiology and nuclear medicine.Results: In the LOCAL survey, 61 valid responses from 26 European countries were received. In almost half of the institutions, hybrid imaging was performed within a single department, mainly in nuclear medicine departments (31%). In half of the centres (51%), PET/CT reports were performed jointly, while in 20% of the centres, reporting was performed by nuclear medicine physicians. Radiologists were responsible for presenting hybrid imaging results in clinical boards in 34% of responding sites. Integrated hybrid imaging training was available in 41% sites. In the NATIONAL survey, responses from 34 countries were received and demonstrated a heterogeneous landscape of official training possibilities in radiology and nuclear medicine with limited opportunities for additional qualifications in hybrid imaging.Conclusions: The results of these surveys demonstrate a notable heterogeneity in the current practice of hybrid imaging throughout Europe. This heterogeneity exists despite the general consensus that strong professional cooperation is required in order to ensure high clinical quality and to strengthen the clinical role of hybrid imaging.
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| 42. |
- Glimelius, Bengt, et al.
(author)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
-
In: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
-
Journal article (peer-reviewed)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 43. |
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| 44. |
- Hartana, C. A., et al.
(author)
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Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer
- 2018
-
In: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 194:1, s. 39-53
-
Journal article (peer-reviewed)abstract
- Tissue-resident memory T (T-RM) cells are CD8(+) T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in T-RM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in T-RM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate T-RM cell phenotypes. We discovered that tumour T-RM cells have low DNA methylation in the PRF1 locus (329% methylation), which corresponds to increased numbers of perforin-expressing T-RM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour T-RM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that T-RM cells from tumours are not terminally exhausted. Moreover, a high number of T-RM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, T-RM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies T-RM cells as potential new targets for cancer immunotherapy.
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| 45. |
- Hartana, Ciputra Adijaya, et al.
(author)
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Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFβ2 mediated pathway
- 2018
-
In: PLOS ONE. - : Public Library Science. - 1932-6203. ; 13:7
-
Journal article (peer-reviewed)abstract
- The immune system plays a significant role in urothelial bladder cancer (UBC) progression, with CD8+ T cells being capable to directly kill tumor cells using perforin and granzymes. However, tumors avoid immune recognition by escape mechanisms. In this study, we aim to demonstrate tumor immune escape mechanisms that suppress CD8+ T cells cytotoxicity. 42 patients diagnosed with UBC were recruited. CD8+ T cells from peripheral blood (PB), sentinel nodes (SN), and tumor were analyzed in steady state and in vitro-stimulated conditions by flow cytometry, RT-qPCR, and ELISA. Mass spectrometry (MS) was used for identification of proteins from UBC cell line culture supernatants. Perforin was surprisingly found to be low in CD8+ T cells from SN, marked by 1.8-fold decrease of PRF1 expression, with maintained expression of granzyme B. The majority of perforin-deficient CD8+ T cells are effector memory T (TEM) cells with exhausted Tc2 cell phenotype, judged by the presence of PD-1 and GATA-3. Consequently, perforin-deficient CD8+ T cells from SN are low in T-bet expression. Supernatant from muscle invasive UBC induces perforin deficiency, a mechanism identified by MS where ICAM-1 and TGFβ2 signaling were causatively validated to decrease perforin expression in vitro. Thus, we demonstrate a novel tumor escape suppressing perforin expression in CD8+ T cells mediated by ICAM-1 and TGFβ2, which can be targeted in combination for cancer immunotherapy.
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| 46. |
- Haylock, Anna-Karin, 1972-
(author)
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Targeting molecules for diagnostics of Head and Neck squamous cell carcinoma
- 2017
-
Doctoral thesis (other academic/artistic)abstract
- To personalize treatment for cancer, correct staging of the primary tumor, nodal disease and metastatic disease is of essence. By targeting tumor specific receptors with radiolabeled antibodies, specificity and accuracy of imaging may be improved. Radio-immunodiagnostics can potentially detect small volume disease, occult metastasis and recurrent cancer in treated tissue. This thesis focuses on evaluation of radio-immunoconjugates directed towards CD44v6, which is a surface receptor overexpressed in many head and neck squamous cell carcinomas. At the outset, the monoclonal chimeric antibody cMab U36 and its cleavage products Fab’ and F(ab’)2 were labeled with 125I and assessed in vitro and in vivo (paper I). The best distribution pattern and tumor to organ ratio was achieved with F(ab’)2. Due to the immunological responses humans can develop towards chimeric antibodies, they are not optimal for clinical use, and subsequently fully human antibody fragments were developed. AbD15179, which is a monovalent fragment, was labeled with 111In and 125I and evaluated in vitro and in mice bearing CD44v6-expressing tumors. Tumor to organ ratios were improved compared to cMab U36 derived fragments, and 111In-AbD15179 displayed a more favorable distribution compared to 125I-AbD15179 (Paper II). A bivalent Fab-dHXL, AbD19384 derived from AbD15179, was then constructed and labeled with 125I and evaluated in cell- and biodistribution studies. Furthermore, an imaging study in a small animal PET was performed with 124I-AbD19384 (Paper III). Uptake in kidneys was reduced and liver uptake increased compared to AbD15179 reflecting the larger molecule. The high CD44v6 expressing tumor was clearly visualized with maximum uptake at 48 hours post injection.In paper IV human single chain fragments towards CD44v6v were selected, and the top candidates A11 and H12 were further evaluated in vitro and in vivo. Single chain fragments are small molecules exhibiting fast clearance and high affinity to the target. The study proved this by demonstrating superior tumor to blood ratios of radiolabeled A11 and H12 compared to previously studied molecules.
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| 47. |
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| 48. |
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| 49. |
- Holmberg, Daniel, et al.
(author)
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Reducing scanning time to 50% for In-111 pentetreotide SPECT when using model-based compensation
- 2012
-
In: 2012 IEEE nuclear science symposium and medical imaging conference record (NSS/MIC). - : IEEE. - 9781467320306 - 9781467320283 ; , s. 2946-2949
-
Conference paper (peer-reviewed)abstract
- In In-111-pentetreotide SPECT, it can be difficult to detect small tumors because of high noise levels and low spatial resolution. The aim of this study was to perform optimization of tumor detection in the liver, with regards to the acquisition and reconstruction protocol for In-111-pentetreotide SPECT with model-based compensation included in the OSEM reconstruction. We were also interested in the effect of performing the examination in half of the time or with half the administered activity. Image reconstruction without model-based compensation was also included for comparison. The study concentrates on the acquired number of projections and the subset size in the OSEM reconstruction, and evaluates contrast as a function of noise for a range of OSEM iterations. The raw-data projections are produced using Monte Carlo simulations of a patient-like anthropomorphic phantom with realistic In-111 pentetreotide uptake, including spherical tumors in the liver. Two collimators are evaluated, the extended low-energy general-purpose (ELEGP) and the medium-energy general-purpose (MEGP) collimator. ELEGP proved to be a better collimator when using model-based compensation. The results also indicate that a relatively low number of subsets is advantageous, and that 60 projection angles or even lower is a better choice than 120. For both collimators the time-reduced scan including model-based compensation was better compared to the full-time reconstructions without model-based compensation.
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| 50. |
- Höglund, Johanna, 0070-
(author)
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On the Use of 76Br-labelled Monoclonal Antibodies for PET : Preclinical Evaluation of Halogenated Antibodies for Diagnosis and Treatment of Cancer
- 2002
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Doctoral thesis (other academic/artistic)abstract
- Radioactive substances are used in vivo to localize and characterize malignant tumours, generally by scintigraphic methods. In this context positron emission tomography (PET) in combination with radiolabelled monoclonal antibodies (mAbs) may provide a sensitive and specific method for detection of cancer. Individual dose calculations, based on such PET measurements, may be carried out to predict the possible use of mAbs labelled with therapeutic nuclides. The positron emitter 76Br, with a half-life of 16 h, is a well-suited candidate for radiolabelling and PET imaging. One drawback of radiobromine is that bromide, the ultimate catabolite after degradation of brominated mAb, is only tardily excreted from the body and is evenly distributed throughout the extracellular space, thereby increasing the background radioactivity. The aim of this work was to produce 76Br-mAb preparations with high accumulation and retention in tumour tissue together with a quick clearance of 76Br-labelled catabolites. Furthermore, the possibility to use brominated or iodinated mAbs in combination with PET to predict 211At-mAb dosimetry was evaluated.Monoclonal Abs directed against colorectal cancer were labelled with 76Br using the direct Chloramine-T-method or indirectly by labelling the precursor molecule N-succinimidyl para-(tri-methylstannyl) benzoate with 76Br, which was subsequently conjugated to the mAbs. Monoclonal Ab A33 labelled with 76Br using the two labelling protocols was characterized in vitro and in vivo in a rat tumour xenograft model. The mAb A33 was also labelled with 125I for comparison. In addition, mAb A33 was labelled with 211At, 125I and 76Br using the indirect labelling protocol and the mAb pharmacokinetics was studied in normal rats in order to estimate if data from brominated or iodinated mAb could be used for dosimetry of 211At in healthy organs and tissue.In conclusion, both direct and indirect labelling resulted in high yields and mAbs with preserved immunoreactivity. In vivo characterization of 76Br-brominated mAb A33 showed that the indirect labelling method makes 76Br-brominated mAb A33 a promising candidate for tumour imaging with PET due to the faster excretion of radiolabelled catabolites compared with direct bromination. Finally, mAb A33 labelled with 76Br and 124/125I can be used to predict the 211At dose of astatinated mAb A33 in most organs given that a correction factor is applied for organs with varying uptake.
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